This proposal will investigate the role of exercise during growth on lifelong skeletal health. Exercise is commonly advocated to address the reduction in bone strength associated with aging as the skeleton adapts to its mechanical environment. However, there is a disparity between when the skeleton is responsive to exercise (adolescence) and when it is prone to fracture (adulthood). This raises the question of whether bone benefits associated with exercise when young persist with aging. We have previously shown in an animal model that exercise when young produces lifelong benefits in cortical bone structure and strength. We hypothesize this also occurs in humans. Mechanical loading associated with exercise induces large increases in cortical bone mechanical properties without substantial increases in quantity (mass) as exercise-induced new bone is deposited at structurally relevant sites on the periosteal surface. As bone loss during aging occurs primarily on the endocortical (and not periosteal) surface, our working hypothesis is that the cortical bone structural changes induced by exercise during adolescence persist long-term and have beneficial effects on estimated bone strength. In contrast, we believe that the skeletal benefits of exercise on trabecular bone will diminish with age due to progressive endocortical bone loss. To investigate the sustainability of exercise- induced changes in bone mass, structure and estimated strength at sites rich in cortical and trabecular bone we will study the midshaft and distal humerus of former major (MLB) and minor (MiLB) league baseball players. These former high-level baseball players are a useful model because: 1) the unilateral upper extremity loading associated with throwing enables the contralateral side to be an internal control; 2) we have shown baseball players have large side-to-side differences in midshaft humeral cortical bone properties; 3) they are exposed to extreme skeletal loading which maximizes skeletal adaptation and reduces the influence of potential cohort differences in activity levels, and; 4) they typically retire completely when they cease playing enabling exploration of the sustainability of exercise effects following loading cessation. In addition to studying the maintenance of exercise effects on the skeleton, we will also perform an initial study to establish: 1) the magnitude of midshaft humeral cortical bone adaptation in currently active MLB/MiLB (male) and National Pro Fastpitch (NPF) (female) players; 2) the influence of playing position on humeral bone adaptation in currently active MLB/MiLB and NPF players, and; 3) that throwing induces distal humeral trabecular bone adaptation (as preliminarily shown by others). In both studies within the proposal, side-to-side differences in habitual loading associated with arm dominance will be corrected for by comparing side-to-side differences in throwers to those in gender- and age-matched controls. PUBLIC HEALTH RELEVANCE: Exercise is commonly prescribed to improve bone health and reduce the risk for osteoporotic fracture associated with aging; however, the skeleton is most responsive to exercise during adolescence (growth) and not when it is prone to osteoporotic fracture in later adulthood. This has raised the question of whether exercise-induced bone changes during adolescence persist into adulthood where they would be most advantageous in reducing bone fracture risk. This proposal will investigate the role of exercise during adolescence on bone health later in life.